Organizational and activational effects of testosterone on carrageenan-induced inflammatory pain and morphine analgesia

Men are typically reported to have higher pain thresholds than women. Gonadal hormones, particularly testosterone for males, may contribute to this effect. This study tested whether changes in the male hormonal milieu early or late in development alter the inflammatory pain induced by carrageenan (CARR, 3%, intraarticular). Male rats were either gonadectomized or sham gonadectomized neonatally. Once adults, the same rats underwent either sham surgery or gonadectomy, and received a testosterone or oil implant. After baseline testing two weeks later, animals were tested in response to mechanical and thermal stimulation following CARR-induced inflammation and injection of saline, 1 mg/kg, or 5 mg/kg morphine. Hormone alterations did not affect baseline responses, but CARR induced mechanical and thermal hyperalgesia in the injured limb. Gonadectomy in adult males injected with saline enhanced inflammation-induced sensitivity to mechanical but not thermal stimulation and the effect was reversed by testosterone. After inflammation, saline-treated males gonadectomized neonatally displayed lower mechanical threshold than control sham animals but this effect was not reversed by testosterone. Both doses of morphine increased mechanical and thermal thresholds. However, compared with the control group, 1 mg/kg morphine was equally effective in reducing mechanical hyperalgesia among groups of animals gonadectomized as adults, but less effective in males gonadectomized neonatally. The results suggest that in males: 1. the antihyperalgesic effect of testosterone (or its metabolites) in CARR-induced inflammation is established during development and maintained by circulating levels of testosterone in adulthood; 2. the nociception-related interaction between the opioid and gonadal systems influences the sensitivity to mechanical stimuli and is likely established during the period of sexual differentiation.